PPP3CA truncating variants clustered in the regulatory domain cause early-onset refractory epilepsy

Undiagnosed Diseases Network, The DDD study

Research output: Contribution to journalArticle (Academic Journal)peer-review

7 Citations (Scopus)

Abstract

PPP3CA encodes the catalytic subunit of calcineurin, a calcium-calmodulin-regulated serine–threonine phosphatase. Loss-of-function (LoF) variants in the catalytic domain have been associated with epilepsy, while gain-of-function (GoF) variants in the auto-inhibitory domain cause multiple congenital abnormalities. We herein report five new patients with de novo PPP3CA variants. Interestingly, the two frameshift variants in this study and the six truncating variants reported previously are all located within a 26-amino acid region in the regulatory domain (RD). Patients with a truncating variant had more severe earlier onset seizures compared to patients with a LoF missense variant, while autism spectrum disorder was a more frequent feature in the latter. Expression studies of a truncating variant showed apparent RNA expression from the mutant allele, but no detectable mutant protein. Our data suggest that PPP3CA truncating variants clustered in the RD, causing more severe early-onset refractory epilepsy and representing a type of variants distinct from LoF or GoF missense variants.

Original languageEnglish
Pages (from-to)227-233
Number of pages7
JournalClinical Genetics
Volume100
Issue number2
Early online date8 Jul 2021
DOIs
Publication statusPublished - Aug 2021

Bibliographical note

Funding Information:
The authors would like to thank the patients and their families for participation in this study. Research reported in this manuscript was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under Award Number U01HG007709. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Keywords

  • calcineurin
  • constitutive activation
  • epileptic syndromes
  • gain-of-function
  • loss-of-function
  • truncating variants

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